ONCOIMMUNOLOGY

2020, VOL. 9, NO. 1, e1826132 (4 pages)

https://doi.org/10.1080/2162402X.2020.1826132

AUTHOR’S VIEW

No time to die: the consensus immunoscore for predicting survival and response to
chemotherapy of locally advanced colon cancer patients in a multicenter
international study
a
Paolo A. Ascierto , Francesco M. Marincolab, Bernard A. Foxc,d, and Jérôme Galon e,f,g

a
Melanoma, Cancer Immunotherapy and Innovative Therapies Unit, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, Napoli, Italy; bRefuge
Biotechnologies, Menlo Park, CA, USA; cDepartment of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR,
USA; dLaboratory of Molecular and Tumor Immunology, Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical
Center, Portland, OR, USA; eLaboratory of Integrative Cancer Immunology, INSERM, Paris, France; fEquipe Labellisée Ligue Contre le Cancer, Paris,
France; gCentre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, Paris, France

ABSTRACT ARTICLE HISTORY

The multicenter international Society for Immunotherapy of Cancer (SITC) study of the consensus Received 14 September 2020
Immunoscore demonstrated the prediction of survival and response to chemotherapy in 763 Stage III Accepted 16 September 2020
colon cancer (CC) patients. Similar Immunoscore groups were found in elderly patients, and densities of KEYWORDS
immune cells and intratumoral T-cell repertoire were not decreasing with age in the tumor microenviron­ Immunoscore; tumor
ment. In two independent cohorts, Immunoscore significantly predicted time to recurrence (TTR), disease- microenvironment;
free survival (DFS), and overall survival (OS), including within high-risk (T4 or N2) and low-risk (T1-3, N1) immunity; cancer
patients. In stratified Cox multivariable analysis for TTR, DFS, and OS, Immunoscore’s association to classification; prognosis;
outcomes was independent of the patient’s age, sidedness, gender, T-stage, N-stage, and microsatellite predictive; colon cancer;
instability status. Furthermore, the relative contribution to the risk test showed that Immunoscore had the phase 3 trial
highest contribution to survival. Importantly Immunoscore predicted the likelihood of response to
chemotherapy. Only patients with a high-Immunoscore significantly benefited from chemotherapy. The
prognostic value of Immunoscore was confirmed in two independent phase 3 clinical trials (NCCTG-
N0147, n = 559; Prodige-IDEA, n = 1062). Moreover, results from IDEA phase 3 randomized trial revealed
the predictive value of Immunoscore for response to adjuvant FOLFOX chemotherapy duration. The latest
edition of the WHO Digestive System Tumors classification introduced the immune response as measured
by Immunoscore as essential and desirable diagnostic criteria for CC, and Immunoscore was introduced
into the 2020 ESMO Clinical Practice Guidelines for CC to refine the prognosis and adjust chemotherapy
decision-making process in stages II and III patients. These results highlight the clinical utility of
Immunoscore.

Clinical utility of immunoscore in stage III colon adaptive immune reaction for the survival of patients revealed
cancer that immune parameters are beyond tumor progression and
invasion (TNM classification). This immune response was
A meta-analysis of the literature including more than 200
defined as the “Immunoscore”.1,5–7
published articles for the implication of cytotoxic T-cells and
The results of an international Immunoscore consortium
T-cell subpopulations with regard to prognosis of cancer
on Stage I/II/III colon cancer patients using the first world­
patients (in 20 different cancer types) revealed that cytotoxic
wide recognized and standardized consensus assay to quan­
CD8 + T-cells were associated with a good prognosis in 97% of
tify the preexisting immunity were published. The results
the studies.1 We previously showed that tumor recurrence and
showed that Immunoscore significantly predicted time to
overall survival times of patients with colon cancer were mostly
recurrence (TTR), disease-free survival (DFS) and overall
dependent on the presence of cytotoxic and memory T cells
survival (OS). Secondly, Immunoscore predicted high-risk
within specific regions of primary tumors. We performed
and low-risk patients in the restricted population of Stage II
a clinical study on human colorectal cancer showing that
colon cancer patients. This established the consensus as
cytotoxic and memory T-cells were predicting the clinical out­
a robust and powerful stratifier to predict the prognosis of
come in early Stage (I/II) colorectal cancer patients. We further
colon cancer patients.8 Before the inclusion of an immune
showed that histopathologic-based prognostic factors of color­
parameter into the TNM-staging system, to move to a TNM-
ectal cancers are associated with the state of the local immune
Immune (TNM-I) classification, it is important to also
reaction. The assessment of CD8(+) cytotoxic T lymphocytes
demonstrate the clinical utility of Immunoscore at each
in combined tumor regions provided an indicator of tumor
stage of the current staging-system. Thus, the clinical utility
recurrence beyond that predicted by AJCC/UICC-TNM
of Immunoscore has been reinforced by the recent publica­
staging.2–4 The importance of the patient intratumor natural
tions demonstrating the prognosis value of Immunoscore in

CONTACT Jérôme Galon jerome.galon@crc.jussieu.fr INSERM, Laboratory of Integrative Cancer Immunology. Cordeliers Research Center, Paris 75006, France
© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits
unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
2 P. A. ASCIERTO ET AL.

Stage III CC patients, and its predictive value in response to
chemotherapy.
Recently, the multicenter international Society for
Immunotherapy of Cancer (SITC) study of the consensus
Immunoscore demonstrated the prediction of survival and
response to chemotherapy in Stage III colon cancer.9 This
international study led by the SITC evaluated the pre-defined
consensus Immunoscore in 763 patients with AJCC/UICC-
TNM Stage III CC from 2 cohorts, a first cohort (Canada/
USA) and a second cohort (Europe/Asia). The consensus
Immunoscore was evaluated by quantifying the CD3+ and
cytotoxic CD8 + T-lymphocyte densities in the tumor and
invasive-margin by digital-pathology using pre-defined cut-
points and categories. The lowest risk of recurrence was
observed in patients with a high-Immunoscore in both cohorts.
Immunoscore Low, Intermediate and High had recurrence-
free rates at 3 y of 56.9%, 65.9%, and 76.4%, respectively, with
a significant hazard-ratio of 0.48 (P= .0003). Significant (all
P< .001) association with prolonged TTR, OS and DFS were
found for patients having a High-Immunoscore .
Immunoscore association to TTR was independent
(P = .0003) of patient’s gender, T-stage, N-stage, sidedness,
and microsatellite instability-status, in Cox multivariable ana­
lysis. Significant association of High-Immunoscore with pro­
longed TTR was also found among MSS patients (P = .0003).
Importantly, Immunoscore had the strongest contribution for
influencing survival (TTR and OS) as measured with Х2 pro­
portion statistical analysis. Patients with a high-Immunoscore
responded to chemotherapy and had prolonged survival com­
pared to patients not receiving chemotherapy. In contrast,
Low-Immunoscore patients did not significantly benefit from
chemotherapy treatment. Furthermore, the predictive value of

Figure 1. Clinical utility of the Immunoscore. (a) Immunoscore and intratumoral T-cell repertoire remain stable with age. (b) Relative contribution of each risk parameter
to survival risk for overall survival in Stage III CC using the x2 proportion test for clinical parameters and Immunoscore. (c) Immunoscore is a powerful prognosis marker
and a predictive marker of response to chemotherapy for stage III colon cancer patients.

a high-Immunoscore for response to chemotherapy and pro­
longed survival was found for both low-risk (T1-3, N1)
(HR = 0.42, P= .001) and high-risk (T4 and/or N2)
(HR = 0.5, P= .001) patients.
This study demonstrated five key findings.9
First, we showed that densities of immune cells and intra­
tumoral T-cell repertoire are not decreasing with age.
Furthermore, the same proportion of Immunoscore groups is
found below 60 y-old and above 85 y-old which is of impor­
tance fundamentally and in considering treatment options.
Second, we demonstrated, in two independent cohorts of
patients from this international study that Immunoscore sig­
nificantly predicted time to recurrence (TTR), disease-free
survival (DFS) and overall survival (OS) in Stage III patients.
Third, we showed that Immunoscore predicted outcome
within the MSS population, and also predicted outcome within
high-risk (T4 or N2) and low-risk (T1-3, N1) stage III patients.
Fourth, in stratified Cox multivariable analysis for TTR,
DFS and OS, Immunoscore’s association to outcomes was
independent of the patient’s age, sidedness, gender, T-stage,
N-stage, and microsatellite instability (MSI) status.
Furthermore, the relative contribution to the risk test showed
that Immunoscore had the highest contribution to survival in
comparison to all other clinical parameters.
Fifth, importantly Immunoscore predicted the likelihood of
response to chemotherapy. Indeed, patients who did not
receive chemotherapy had similar outcomes as those who
received chemotherapy, if they had a low-Immunoscore, and
did not significantly benefit from chemotherapy. In contrast,
patients with an Intermediate/high-Immunoscore significantly
benefited from chemotherapy.
This illustrates the fact that the benefit of chemotherapy
may be dependent upon a proper preexisting immunity
(Figure 1).
Validation in two randomized phase 3 trials
The results of Immunoscore in Stage III CC patients were
confirmed in two independent randomized phase 3 clinical
trials. The Immunoscore-N0147 study was conducted in colla­
boration with clinicians and researchers from the Mayo
Clinic.10 The study included 559 patient samples from the
FOLFOX arm of the NCCTG-N0147 trial and used the pre-
defined consensus Immunoscore. Immunoscore predicted
relapse and death in stage III CC patients treated with
a standard adjuvant treatment combining fluoropyrimidine
and oxaliplatin in the N0147 trial.10 Another randomized
phase 3 clinical trial (IDEA) in 1062 Stage III CC patients
tested the consensus Immunoscore.11 The two studies were
performed, using the pre-defined consensus Immunoscore,
had similar significant results regarding the prognostic value
of Immunoscore.
The randomized phase 3 clinical trial IDEA aimed to
evaluate the non-inferiority of 3 months of chemotherapy
(FOLFOX or CAPOX) compared to 6 months. The primary
objective of this trial (IDEA) was not met, and it could not
be concluded that this non-inferiority was achieved.
However, the IDEA study showed that 3 months adjuvant
treatment was associated with a significantly lower
ONCOIMMUNOLOGY 3
incidence and severity of adverse events compared to
6 months. Even if the primary objective of this trial was
not met, secondary subgroup analyses were carried out and
showed that CAPOX met the criteria for non-inferiority,
but not those for FOLFOX. Differences in DFS depending
on treatment-duration were modest. Based on these data it
was proposed to treat low-risk patients (T1-3N1) with
3 months of chemotherapy. However, this study highlighted
the need for additional biomarkers to predict the efficacy of
adjuvant chemotherapy in CC patients.
Not only the phase 3 trial IDEA confirmed the prognostic
value of Immunoscore but it also confirmed its predictive value
in response to chemotherapy.11 High-Immunoscore patients
significantly benefited from 6-month treatment compared to
3month treatment. Conversely, in patients with Low-
Immunoscore, no significant benefit of 6-month FOLFOX
was observed compared to 3-month treatment. These results
were also observed independently of the clinical stage. Both
high-risk (T4 and/or N2) and low-risk (T1-3, N1) patients sig­
nificantly benefited from 6-month FOLFOX when they had
a High-Immunoscore, but not when they had a Low-
Immunoscore. This validated and further demonstrated the
predictive value of Immunoscore in response to chemotherapy.
Importantly, clinically low-risk patients (T1-3, N1) with High-
Immunoscore had 91.4% DFS at 3-y when treated with the
6-month FOLFOX, but only 80.8% with the 3-month treatment
regimen. Thus, even low-risk (T1-3, N1) patients with a High-
Immunoscore could effectively benefit from 6 months of
FOLFOX, thereby changing clinical practice. Unfortunately,
patients with Low-Immunoscore (44.6% of Stage III) not only
had an increased risk of recurrence but also a lack of benefit
from longer duration of chemotherapy treatment. Given the
poor outcome in these patients, new therapeutic strategies and
clinical trials should be initiated in this population. FOLFOX
chemotherapy contains 5-fluorouracil and Oxaliplatin. These
components may have a dual impact on the immune system.
On one hand, 5-fluorouracil may partially deplete or transi­
ently inactivate inhibitory immune cells, and on the other hand
oxaliplatin may increase cytotoxic T-cell infiltration and
induce immunogenic cell death (ICD).12–14 It could be
hypothesized that ICD-driven immunity is inefficient in
tumors with a weak preexisting immunity such as Low-
Immunoscore patients. Thus, it will be important to identify
Immunoscore-Low patients to test combination immu­
notherapies that can prime and expand anti-cancer immunity
in this population, in order to prolong their survival.
Conclusions
These results highlight the prognostic value of Immunoscore
regardless of the patient’s age. It further strengthens the Level
of Evidence and clinical utility of Immunoscore in stage III CC
patients. The Immunoscore assay has been developed as an
in vitro diagnostic test (CE-IVD) and is available in FDA CLIA-
certified laboratories for routine use. Importantly, in the latest
(5th) edition of the WHO Digestive System Tumors classifica­
tion, was introduced “the immune response as essential and
desirable diagnostic criteria for colorectal cancer,” and citing the
consensus Immunoscore as best clinical evidence in colon
4 P. A. ASCIERTO ET AL.
cancer. Furthermore, Immunoscore was introduced into the
2020 ESMO Clinical Practice Guidelines for colon cancer to
refine the prognosis and thus adjust the chemotherapy decision-
making process in stage II and even in low-risk stage III patients.
The results of Immunoscore in the multicenter international
SITC study and the recent inclusions into WHO and ESMO
guidelines argue for the benefit of implementing the
Immunoscore in clinical practice and for its introduction in
a new TNM-Immune (TNMI) classification system.
Acknowledgments
The authors thank the patients, their caregivers, the GERCOR team, the
PRODIGE investigators, the Mayo clinic investigators, and SITC
Immunocore consortium investigators.
Disclosure of potential conflicts of interest
JG has patents associated with the immune prognostic biomarkers. JG is
co-founder of HalioDx biotech-company. Immunoscore® a registered tra­
demark owned by the National Institute of Health and Medical Research
(INSERM) licensed to HalioDx.
Funding
The work was supported by INSERM, the LabEx Immuno-oncology, the
Transcan ERAnet European project, the Society for Immunotherapy of Cancer
(SITC), Association pour la Recherche contre le Cancer (ARC), CARPEM, AP-
HP, HalioDx, and Institut National du Cancer, France (INCa).
ORCID
Paolo A. Ascierto http://orcid.org/0000-0002-8322-475X
Jérôme Galon http://orcid.org/0000-0001-9635-1339
References
1. Bruni D, Angell HK, Galon J. The immune contexture and
Immunoscore in cancer prognosis and therapeutic efficacy. Nat
Rev Cancer. 2020. doi:10.1038/s41568-020-0285-7. PMID:
32753728.
2. Bindea G, Mlecnik B, Angell HK, Galon J. The immune landscape of
human tumors: implications for cancer immunotherapy.
Oncoimmunology. 2014;3:e27456. doi:10.4161/onci.27456. PMID:
24800163.
3. Bindea G, Mlecnik B, Fridman WH, Galon J. The prognostic
impact of anti-cancer immune response: a novel classification of
cancer patients. Semin Immunopathol. 2011;33:335–340.
doi:10.1007/s00281-011-0264-x. PMID: 21461991.
4. Pages F, Galon J, Fridman WH. The essential role of the in situ
immune reaction in human colorectal cancer. J Leukoc Biol.
2008;84:981–987. doi:10.1189/jlb.1107773. PMID: 18559950.
5. Angell HK, Bruni D, Barrett JC, Herbst R, Galon J. The immu­
noscore: colon cancer and beyond. Clin Cancer Res.
2020;26:332–339. doi:10.1158/1078-0432.ccr-18-1851. PMID:
31413009.
6. Galon J, Bruni D. Tumor Immunology And Tumor Evolution:
Intertwined Histories. Immunity. 2020;52:55–81. doi:10.1016/j.
immuni.2019.12.018. PMID: 31940273.
7. Kirilovsky A, Marliot F, El Sissy C, Haicheur N, Galon J, Pages F.
Rational bases for the use of the immunoscore in routine clinical
settings as a prognostic and predictive biomarker in cancer
patients. Int Immunol. 2016;28:373–382. doi:10.1093/intimm/
dxw021. PMID: 27121213.
8. Pages F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C,
Lugli A, Zlobec I, Rau TT, Berger MD, et al. International
validation of the consensus immunoscore for the classification
of colon cancer: a prognostic and accuracy study. Lancet.
2018;391:2128–2139. doi:10.1016/S0140-6736(18)30789-X.
PMID: 29754777.
9. Mlecnik B, Bifulco C, Bindea G, Marliot F, Lugli A, Lee JJ,
Zlobec I, Rau TT, Berger MD, Nagtegaal ID, et al. Multicenter
international society for immunotherapy of cancer study of the
consensus immunoscore for the prediction of survival and
response to chemotherapy in stage III colon cancer. J Clin
Oncol. 2020;JCO1903205. doi:10.1200/JCO.19.03205. PMID:
32897827.
10. Sinicrope FA, Shi Q, Hermitte F, Zemla TJ, Mlecnik B,
Benson AB, Gill S, Goldberg RM, Kahlenberg MS, Nair SG,
et al. Contribution of immunoscore and molecular features to
survival prediction in stage III colon cancer. JNCI Cancer
Spectr. 2020;4:pkaa023. doi:10.1093/jncics/pkaa023. PMID:
32455336.
11. Pagès F, André T, Taieb J, Vernerey D, Henriques J, Borg C,
Marliot F, Ben Jannet R, Louvet C, Mineur L, et al. Prognostic
and predictive value of the Immunoscore in stage III colon
cancer patients treated with oxaliplatin in the prospective IDEA
France PRODIGE-GERCOR cohort study. Ann Oncol.
2020;31:921–929. doi:10.1016/j.annonc.2020.03.310. PMID:
32294529.
12. Aranda F, Vacchelli E, Eggermont A, Galon J, Sautes-Fridman C,
Tartour E, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: peptide
vaccines in cancer therapy. Oncoimmunology. 2013;2:e26621.
doi:10.4161/onci.26621. PMID: 24498550.
13. Vacchelli E, Galluzzi L, Fridman WH, Galon J, Sautes-Fridman
C, Tartour E, Kroemer G. Trial watch: chemotherapy with
immunogenic cell death inducers. Oncoimmunology.
2012;1:179–188. doi:10.4161/onci.1.2.19026. PMID: 22720239;.
2011ONCOIMM0105. .
14. Vacchelli E, Senovilla L, Eggermont A, Fridman WH, Galon J,
Zitvogel L, Kroemer G, Galluzzi L. Trial watch: chemotherapy
with immunogenic cell death inducers. Oncoimmunology.
2013;2:e23510. doi:10.4161/onci.23510. PMID: 23687621.